Tetra Discovery Partners was the recipient of an NIH Blueprint Neurotherapeutics Network award to develop a phosphodiesterase-4D (PDE4D) allosteric inhibitor for treating cognitive impairment in patients affected by psychiatric and neurologic diseases. The Tetra-NIH Blueprint drug, BPN14770, currently is in human Phase 2 clinical trials for the treatment of Fragile X Syndrome and Alzheimer?s disease and has received US FDA Orphan Drug Designation in Fragile X Syndrome. The Phase II SBIR project will develop a phosphodiesterase-4D (PDE4D) PET tracer for imaging the distribution of the enzyme in human brain. Human studies with the PDE4D PET tracer may benefit patients by improving understanding of how changes in cAMP signaling and altered regulation of PDE4 subtypes contribute to the pathophysiology of disease. The PET tracer also will be useful for determining the dose of BPN14770 to be used in pivotal human clinical trials by assessing PDE4D target occupancy in brain. The target occupancy study adds value to the BPN14770 neurotherapeutic and is a critical gate keeper for partnering the drug program with a larger pharmaceutical company. Human studies with the first PDE4D PET tracer developed by the company revealed an intriguing pattern of specific PDE4D binding in regions of the brain known to be important for cognition, namely prefrontal cortex, temporal cortex and hippocampus. However, accumulation of radiolabeled metabolites precluded further advancement of the compound. The Phase II SBIR proposes a straightforward chemical optimization strategy to address this issue. The goal of the Phase II SBIR is to optimize a PDE4D PET ligand for advancement into human clinical trials.